Breast cancer is among the most common malignant tumors and is the leading cause of death from cancer among women. The incidence of breast cancer has been steadily increasing over the past fifty years. Worldwide, it is estimated that more than one million women are diagnosed with breast cancer every year, and more than 410,000 will die from the disease. Various risk factors can increase a woman's chance of developing breast cancer, such as age, personal and family history of breast cancer, exposure to radiation, social and economical class, pregnancy, menarche, menopause, and age of first pregnancy. Tobacco, one of the most widely examined environmental factors, contains human carcinogens that contribute to a woman's risk of developing breast cancer. Epidemiological cohort studies with large numbers of participants in the United States and Japan have indicated that breast cancer risk is associated with active and passive smoking.
Previous studies using a soft agar transforming assay and a mouse xenograft model demonstrated that noncancerous MCF-10A human breast epithelial cells can become neoplastically transformed by exposure to either a cigarette smoke condensate or the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (Mei J, Hu H, McEntee M, et al. Breast Cancer Res Treat 2003; 79(1):95-105; Siriwardhana N, Choudhary S, Wang H C. Breast Cancer Res Treat 2008; 109(3):427-41). In vivo studies have demonstrated that nicotine promotes the growth of solid tumors, suggesting that nicotine might contribute to the progression of cell proliferation, invasion, and angiogenesis in tumors.
Human neuronal tissues have been reported to have the most abundant expression of the nicotinic acetylcholine receptor (nAChR) subunit. These nAChRs occur as heteropentamers comprised of a combination of α subunits (α1-α6) and β subunits (β2-β4) or as homopentamers derived from subunits α7-α10 symmetrically arranged around a central ion pore. However, reverse transcription-polymerase chain reaction (RT-PCR), immunoblotting, and flow cytometry analyses have provided considerable evidence for the expression of nAChRs in nonneuronal cells outside of the nervous system, including bronchial epithelium membranes and endothelial cells (West K A, Brognard J, Clark A S, et al. J Clin Invest 2003; 111(1):81-90; Egleton R D, Brown K C, Dasgupta P. Trends Pharmacol Sci 2008; 29(3):151-8.) The physiological ligand of nAChRs is acetylcholine; however, tobacco components such as nicotine and NNK are also known to be high affinity nAChR agonists (Schuller H M. Life Sci 2007; 80(24-25):2274-80; Schuller H M, Orloff M. Biochem Pharmacol 1998; 55(9):1377-84.) Cigarette smoking is known to be a prominent risk factor for lung, colon, and bladder cancers, all of which express α7 as a major nAChR, as well as breast cancers, which express α9-nAChR, suggesting that agents such as nicotine and NNK may function in a receptor-dependent manner (Wong H P, Yu L, Lam E K, et al. Toxicol Sci 2007; 97(2):279-87; West K A, Brognard J, Clark A S, et al. J Clin Invest 2003; 111(1):81-90; Wong H P, Yu L, Lam E K, et al. Toxicol Appl Pharmacol 2007; 221(3):261-7; Chen R J, Ho Y S, Guo H R, et al. Toxicol Sci 2008; 104(2):283-93.) Yung-Leun Shih et al. indicates that nicotine significantly increased α9-nAChR mRNA and protein expression levels in human breast cancer cells (Yung-Leun Shih et al., J. Agric. Food. Chem. 2010, 58, 235-241). However, the reference is silent on the relationship of expression of α9-nAChR and tumorigenesis of breast cancer. Ching-Shyang Chen et al. elucidate whether Nic/nicotinic acetylcholine receptor (nAChR) binding could affect cyclin D3 expression in human breast cancer cells and the carcinogenic role of cyclin D3. The cyclin D3 expression cannot suggest the overexpression and activation of α9-nAChR per se.
Unlike the nAChRs that are expressed in normal neuronal cells, most of the nAChRs present in cancer cell lines have not been functionally characterized (Egleton R D, Brown K C, Dasgupta P. Trends Pharmacol Sci 2008; 29(3):151-8.) In cancer cells, nAChRs could also play a role in the acquisition of chemotherapy drug resistance. Nicotine has been shown to protect cells against apoptosis, so nAChR antagonists could potentially be used in combination with established chemotherapeutic drugs to enhance therapeutic response to chemotherapy.
The ability to identify breast cancer patients with more aggressive diseases is crucial to accurate prognosis and planning for adequate treatment. Identifying the alterations in gene expression which are associated with malignant tumors, including those involved in tumor progression, is clearly a prerequisite not only for a full understanding of cancer, but also to develop new rational therapies against cancer. Unfortunately, there is presently no sufficiently accurate method of determining malignant progression and metastatic potential of breast cancer.